The cellular and molecular adaptations that occur as a result of repeated cocaine exposure are poorly understood. These neuroadaptations likely contribute to the perpetuation of cocaine addiction by mediating the processes of drug dependence, withdrawal, and craving. The ability of cocaine to enhance dopaminergic neurotransmission in the mesocorticolimbic pathway undoubtedly plays a critical role in the initial reinforcing properties of this drug. However, other neurotransmitter systems are also integral to the addiction process. One such system is the endogenous opioid system. It has been long appreciated that opioids and dopamine together mediate emotional and reinforced behaviors and locomotion, however the exact nature of their interactions as related to cocaine addiction has not been elucidated. Results from experiments proposed herein will fill this gap in our knowledge. Previous studies from out lab have demonstrated that chronic cocaine administration alters the expression and function of mu opioid receptors in brain regions involved in cocaine addiction. Specifically, cocaine produces an upregulation of mu receptors in areas of the nucleus accumbens, caudate putamen, anterior cingulate cortex, and basolateral amygdala. Our preliminary data support the overall hypothesis that cocaine administration results in an indirect activation of mu opioid receptors which potentiates the effects of dopamine. With chronic cocaine administration, mu receptors become upregulated in number and function. Increases in mu receptor activity leads to enhanced responses to further cocaine administration contributing to behavioral sensitization. To test this hypothesis, the following specific aims are proposed: 1. To determine the role of mu opioid receptors in the behavioral effects of cocaine; 2. To determine the molecular and cellular mechanisms of cocaine-induced mu receptor upregulation; and 3. To determine the functional significance of cocaine-induced mu receptor upregulation. The combined results from these studies will elucidate the molecular interactions between dopaminergic and opioid systems as related to cocaine addiction and delineate the role of the mu opioid receptor in cocaine- mediated behaviors.